ACSM5

Chr 16

acyl-CoA synthetase medium chain family member 5

NCBI Gene: 54988 ENSG00000183549 UniProt: Q6NUN0 OMIM: 614361

ACSM5 encodes an enzyme that catalyzes the activation of fatty acids by CoA to produce acyl-CoA, the first step in fatty acid metabolism within mitochondria. Mutations cause autosomal recessive spastic paraplegia-56, which involves progressive spasticity and weakness primarily affecting the lower limbs. This gene shows low constraint against loss-of-function variants, consistent with recessive inheritance patterns.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable fatty acid ligase activity and fatty-acyl-CoA synthase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid biosynthetic process. Located in mitochondrion. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.26

Clinical Summary— ACSM5

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

79 VUS of 101 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.26LOEUF

pLI 0.000

Z-score 0.40

OE 0.92 (0.69–1.26)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.62Z-score

OE missense 1.10 (1.00–1.19)

367 obs / 335.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.92 (0.69–1.26)

0≤0.351.4

Missense OE?1.10 (1.00–1.19)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 29 / 31.4Missense obs/exp: 367 / 335.0Syn Z: -2.11

This gene — mechanism propensity

0.6743th %ile

GOF

0.6053th %ile

LOF

0.4037th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

101 submitted variants in ClinVar

ClinVar

Classification Summary

VUS79

Likely Benign6

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	79	0	0	79
Likely Benign	4	0	2	6
Benign	1	1	0	2
Total	84	1	2	87

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap ACSM5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →